Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo

Whitney A Bullock; April M Hoggatt; Daniel J Horan; Andrew J Elmendorf; Amy Y Sato; Teresita Bellido; Gabriela G Loots; Fredrick M Pavalko; Alexander G Robling

doi:10.1016/j.isci.2019.09.023

Lrp4 Mediates Bone Homeostasis and Mechanotransduction through Interaction with Sclerostin In Vivo

iScience. 2019 Oct 25:20:205-215. doi: 10.1016/j.isci.2019.09.023. Epub 2019 Sep 18.

Authors

Whitney A Bullock¹, April M Hoggatt¹, Daniel J Horan¹, Andrew J Elmendorf¹, Amy Y Sato¹, Teresita Bellido¹, Gabriela G Loots², Fredrick M Pavalko³, Alexander G Robling⁴

Affiliations

¹ Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr., MS 5035, Indianapolis, IN 46202, USA.
² Physical and Life Sciences, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA.
³ Department of Integrative and Cellular Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana Center for Musculoskeletal Health, Indianapolis, IN 46202, USA.
⁴ Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr., MS 5035, Indianapolis, IN 46202, USA; Indiana Center for Musculoskeletal Health, Indianapolis, IN 46202, USA; Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA. Electronic address: arobling@iupui.edu.

Abstract

Wnt signaling plays a key role in regulating bone remodeling. In vitro studies suggest that sclerostin's inhibitory action on Lrp5 is facilitated by the membrane-associated receptor Lrp4. We generated an Lrp4 R1170W knockin mouse model (Lrp4^KI), based on a published mutation in patients with high bone mass (HBM). Lrp4^KI mice have an HBM phenotype (assessed radiographically), including increased bone strength and formation. Overexpression of a Sost transgene had osteopenic effects in Lrp4-WT but not Lrp4^KI mice. Conversely, sclerostin inhibition had blunted osteoanabolic effects in Lrp4^KI mice. In a disuse-induced bone wasting model, Lrp4^KI mice exhibit significantly less bone loss than wild-type (WT) mice. In summary, mice harboring the Lrp4-R1170W missense mutation recapitulate the human HBM phenotype, are less sensitive to altered sclerostin levels, and are protected from disuse-induced bone loss. Lrp4 is an attractive target for pharmacological targeting aimed at increasing bone mass and preventing bone loss due to disuse.

Keywords: Biological Sciences; Cell Biology; Molecular Biology.

Abstract

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